Development of myocarditis and pericarditis after COVID-19 vaccination in adult population: A systematic review

Objectives A clear temporal relationship between myocarditis and pericarditis after COVID-19 vaccination has led to the belief that the vaccine may act as a trigger for these cardiologic complications. The aim of this systematic review is to explore the incidence, clinical presentation, management, and association between them. Methods We conducted a systematic literature search on Cochrane, MEDLINE, and EMBASE as per guidelines of PRISMA (Preferred Reporting Items for Systematic Reviews). A total of 41 case reports and case series describing 97 patients, and 5 original articles describing 15,585,309 participants were selected as part of this review. Results Of the 97 reported cases describing vaccine-associated myocarditis/pericarditis, 67 (69%) patients received Pfizer-BioNTech and 25 (25.7%) received Moderna. The mean onset of symptoms after vaccine administration was 3.8 ± 4.5 days with three-quarters developing symptoms after the second dose. Chest pain (n = 88, 90%) and fever (n = 33, 34%) were the most common presenting complaints. Out of 97, 80 (82.5%) patients recovered while 4 (4.1%) patients expired. The pooled incidence of myocarditis and pericarditis extrapolated from original studies is 0.001% and 0.0004%, respectively. In the original studies, nearly all the cases of myocarditis and pericarditis were mild. Chest pain and fever were the most common presenting symptoms. Conclusion Myocarditis and pericarditis after the COVID-19 vaccine have been reported more in young adult males and are most likely to occur after the second dose of mRNA vaccines. The presentation is mild and the majority of the patients recover either completely or partially.


Introduction
Myocarditis is the inflammation of the myocardium that occurs most commonly due to viral illnesses although non-infectious etiologies have also been reported. It is believed that myocarditis and its complications are largely immune-mediated [1]. Myocarditis usually presents with chest pain, which can result from associated pericarditis, or occasionally, from coronary artery spasm. Acute myocarditis is frequently first diagnosed as nonischemic dilated cardiomyopathy in a symptomatic patient [2]. Pericarditis (inflammation of the pericardium) commonly presents with sharp, retrosternal chest pain that is relieved by sitting or leaning forward but gets exacerbated in the supine position, by coughing, and with inspiration [3].
COVID-19, caused by the novel coronavirus SARS-CoV-2, became a public health emergency of international concern (PHEIC) in January 2020 [4]. According to the latest statistics, over 317 million global cases of SARS-CoV-2 have been reported so far. Mass immunization campaigns have been initiated throughout the world as per the World Health Organization (WHO) recommendations. Multiple coronavirus vaccines are currently being administered throughout the world which includes mRNA based vaccines, (i.e. Pfizer-BioNTech, Moderna), recombinant adenoviral vector vaccines (i.e. Johnson & Johnson/Janssen, Oxford-AstraZeneca and Sputnik V), and the inactivated whole viral vaccines (i.e. Sinovac Biotech and Sinopharm) [5]. Given the rapid global spread and increased associated mortality, the emergency use approval was granted to COVID-19 vaccines before the completion of conventional and robust phases of clinical trials [6]. Therefore, some concerns have been raised regarding the safety as well as the efficacy of these vaccines.
Numerous case reports, case series, and retrospective studies have now suggested a possible link between myocarditis and Covid-19 mRNA vaccination. To explore this phenomenon, we planned to conduct a systematic review in which databases would be thoroughly searched to find out all literature available on post-vaccination myocarditis and pericarditis in adults. A compilation of all such cases will alert the physicians about rare but detrimental side-effects of vaccination and enhance their knowledge regarding the likely clinical presentation, prognosis, and management. The timely diagnosis followed by prompt treatment will ultimately lead to improved patient care.
Several other reviews have reported adverse events after COVID-19 vaccination [7]. To date, only one systematic review and meta-analysis evaluating myocarditis following COVID-19 vaccination has been published in the literature [8]. However, the review included a limited number of cases, focused only on mRNA vaccines, and lacked sufficient discussion on underlying pathogenic mechanisms. This indicates the need for a more comprehensive evidence synthesis that includes original articles and updated evidence. This systematic review aims to provide a detailed account of the development of myocarditis and pericarditis following the COVID-19 vaccination, and serves as a guide for researchers for re-evaluation, who may need to take into consideration this side-effect while developing new vaccines.

Methods
This systematic review is compliant with the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) guidelines and has been registered with The International Prospective Register of Systematic Reviews (PROSPERO: CRD42021276596) [9] (Supplementary file_3).

Search strategy
The systematic literature search was conducted on the following three databases: MEDLINE (via PubMed), Cochrane, and Embase without any restriction of language, study design, country, and year of publication. The complete search string for PubMed is given in Table 1.

Study selection and data extraction
We considered all the peer-reviewed published studies that included the adult population (>19 years) who developed myocarditis and pericarditis following any type (mRNA, viral vector, and protein subunit) of COVID-19 vaccine. Review articles, editorials, preprints and those original articles that reported other side effects of vaccination but did not discuss myocarditis and pericarditis specifically were excluded. This review only included articles written in English language.
Articles were searched and extracted by two reviewers (M.F and H.A. C), and a third investigator (M.H.A.K) was there to resolve any discrepancies. Identified studies were uploaded to Mendeley and duplicates were removed. Initially, the articles were screened based on title and abstract, after which the full articles were reviewed. The retrieved results are summarized in the form of two tables. One table focuses on the demographics, medical history, and outcomes, whereas the second is based on relevant medical investigations and diagnostic findings. Continuous variables are presented as means ± standard deviations, and categorical variables are presented as absolute values and percentages. Microsoft Excel was used for data extraction and calculations carried out in this study. The references were added through Mendeley.

Quality appraisal
The quality of the included articles was assessed by the Joanna Briggs Institute Critical Appraisal Tool for case reports and case series and the Newcastle-Ottawa Scale quality assessment scale for cohorts (available in Supplementary file_1) [10,11]. Three reviewers (M.F, U.H, M.H.A.K) first independently scored each article and then awarded a consensus score to each. The score report is provided in the supplementary files. Due to large heterogeneity between study designs, study populations, outcomes, and outcome measures, a meta-analysis could not be performed. The systematic review has been self-evaluated through the AMSTAR 2 checklist (available in Supplementary file_2) [12]. As no Randomized Controlled trial was included in the review, the level of compliance with AMSTAR 2 came out to be "moderate".

Results
The search of three databases identified 250 articles. Seventy-one articles were removed due to duplication and 96 articles were excluded due to irrelevance to the topic. After rigorous screening, 46 articles comprising case series, case reports [2, and original articles [53][54][55][56][57] were included in our review (Fig. 1).

Case series and case reports
A total of 97 patients were described in 41 case series and case reports. The demographic characteristics, clinical presentation, lab investigations, radiological findings, and treatment of the 97 patients have been elaborated in the form of two tables (Tables 2 and 3).

Discussions
This systematic review summarized evidence from the original studies, case reports, and case series which discussed the development of myocarditis and pericarditis following COVID-19 vaccination. This will keep physicians up-to-date regarding the complications and side effects of newly introduced COVID-19 vaccines. We found that males are notably more likely to develop myocarditis and pericarditis following COVID-19 vaccination than females (85% vs 15%). The majority of the patients had no significant history of COVID-19 infection or any other cardiovascular disease. The prevalence of myocarditis and pericarditis was more among the patients who received Pfizer-BioNTech (BNT162b2) than those who received other vaccines, but this may be due to the fact that more patients included in this review had received the aforementioned vaccine. Similarly, a greater percentage of patients who developed the symptoms received two doses of vaccine (compared to one). Chest pain, fever, myalgias, and dyspnoea were the most common presentations. The majority of the patients who presented with myocarditis and pericarditis had a good recovery and were discharged.
Several hypotheses have been put forward to explain the factors that might cause these complications of the COVID-19 vaccine. However, the exact pathophysiology is yet to be elaborated. One of the proposed mechanisms is the interaction between components of the vaccine and the susceptibility of the subject known as molecular mimicry. Due to the similarity between the pathogenic component of the vaccine and specific human proteins, there is immune cross-reactivity resulting in autoimmune disease [58,59]. Among other vaccines for which myocarditis has been reported as an adverse effect, only the smallpox vaccine has demonstrated a significantly high risk [60]. However, the smallpox vaccine differs from the COVID vaccine both in composition and elicitation of a specific immune response.
The higher prevalence of this condition among males can be explained based on the role played by variations in hormone signalling. Testosterone has the ability to suppress anti-inflammatory immune cells while promoting a more aggressive T helper 1 cell immunological response. Oestrogen, on the other hand, inhibits pro-inflammatory T cells, resulting in a reduction in cell-mediated immune responses [59]. However, further research is required to explore the exact phenomenon.
The incidence of myocarditis following the second dose is greater, probably because of a phenomenon called hypersensitivity myocarditis, with the first dose presenting as a sensitising dose [61]. More prevalence of myocarditis and pericarditis among the patients who received Pfizer-BioNTech (BNT162b2) and Moderna (mRNA 1273) indicates that mRNA vaccines are associated with a higher risk of developing myocarditis than the viral vector vaccines like AstraZeneca and The Janssen/Johnson & Johnson [62]. Bozkurt et al. has proposed that autoantibody generation and subsequent attack on cardiac myocytes in response to mRNA vaccine underlie this increased risk [63]. Larger scale studies have indicated myocarditis and pericarditis to be rare adverse events of the COVID-19 vaccine. The US population-based study has reported the incidence rate of myocarditis and pericarditis to be 5.73 to 26 cases per 100,000 person-year and 0.95 to 2.16 cases per 100,000 person-year, respectively [64]. Another study conducted in Israel has reported the cumulative incidence rate to be 2.13 (1.56-2.70) per 100, 000 [65]. Most patients underwent CMR imaging revealing myocardial edema and hyperaemia, findings supportive of myocarditis. CMR imaging has an important role in therapeutic decision-making in patients with suspected myocarditis. It acts as a predictor of functional and clinical recovery and the CMR-visualised pattern of myocardial damage provides some insight into the underlying illness aetiology and pathogenesis [66]. As the CMR imaging of patients was performed in an acute setting, it was difficult to assess the actual degree of damage and prognosis and highlight etiological and pathological factors that may be at play [67]. NSAIDs, colchicine, and steroids were the most commonly employed treatments in the case studies, suggesting that the management of post-COVID vaccine myocarditis is in line with the current guidelines. The good prognosis and recovery of patients in most cases corroborate this fact as well. The effectiveness of anti-inflammatory drugs also backs the theory of molecular mimicry and autoimmunity in C-VAM (COVID vaccine-associated myocarditis).
Practising physicians and healthcare providers can benefit from the information included in this study by providing improved consultation on vaccine safety and potential side effects. Healthcare providers should discuss all the possible risk factors before choosing the specific type of vaccine. The viral vector vaccine can be an alternative for patients with increased risk of myocarditis/pericarditis, or for those who have a history of cardiomyopathy … The main limitation of this review is that no large-scale clinical trial investigating the risk factors, clinical presentation, and prognosis of patients developing myocarditis and pericarditis following COVID-19 vaccination has been conducted so far so only case reports, case series, and cohort studies have been included in the review. Moreover, there is inherent heterogeneity owing to the individual nature of every patient included in the case report and case series. Lastly, mild cases of myocarditis and pericarditis remain unreported and due to the recent nature of the condition, there is insufficient evidence to expound on the underlying pathogenic mechanisms. There is a significant potential for publication bias because rare events and diagnostically unique cases are more likely to be reported and published.

Conclusion
Myocarditis and pericarditis after the COVID-19 vaccine occur most commonly in adult males after the second dose of mRNA vaccines (Pfizer and Moderna). The presentation is usually mild, and the majority of patients have a good recovery. Cell-mediated immune responses generated by the body against the vaccine components cross-react with cardiac cells to cause myocardial and pericardial inflammation. It follows that the most effective treatment for this clinical entity are immunosuppressants and anti-inflammatory agents (e.g., colchicine, NSAIDs and steroids). Physicians should consider myocarditis and pericarditis as a probable diagnosis in patients who have received COVID-19 vaccines, especially in males who develop suggestive symptoms after a second dose of Pfizer and Moderna. Viral vector vaccines may be a better alternative for patients with a history of cardiac diseases.

Ethical approval
This is a systematic review and did not require ethical approval.

Sources of funding
This research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contribution
MF and HAC conceived the idea established a search strategy. MF, MHAK and MSA retrieved the articles, and screened them for relevancy. After selecting relevant articles, MWM, UH and HS ran quality assessment on the included articles. Data was extracted by MF, UH, MHAK and HS. HF and MAUR proofread the extracted data and matched it with articles to eliminate errors. MF and MHAK then worked on the write up. MAUR, HF and HAC provided critical assistance in proof reading and editing of the write up. All the authors approved the final version of the article.
Guarantor I, Maurish Fatima, the corresponding author for this review accept my role as the Guarantor for this research.

Consent
This is a systematic review, where authors verified that proper consent was obtained from patients in all of the studies included.

Provenance and peer review
Not commissioned, externally peer-reviewed.